The role of γ-aminobutyric acid in tumor immunity / 药学学报

italic>γ-Aminobutyric acid (GABA) is a crucial inhibitory neurotransmitter found in various cells in the human body. While the GABAergic system is typically associated with the nervous system, recent research has revealed that immune cells and tumor cells also express components of this system. In the tumor microenvironment (TME), GABA is secreted to act extracellularly on other cells. GABA is metabolized via the GABA shunt and is involved in the tricarboxylic acid (TCA) cycle by generating succinate, which can provide energy for tumor cells. Activation of GABA receptors (GABARs) is a major pathway through which GABA participates in the regulation of antitumor immune responses. The activation of GABA type A receptors (GABAARs) can inhibit the activation and proliferation of T cells, elicit anti-inflammatory macrophages, and promote tumor cell growth and migration, while activation of GABA type B receptors (GABABRs) is generally considered to inhibit cancer cell migration and induce cancer cell apoptosis. In general, receptor activation inhibits immune cells, but the effect on tumor cells varies. Additionally, the downregulation of the expression levels of GABA transporters (GATs) is involved in tumor progression. Although antagonists of GABA metabolism and drugs that act on GABA receptors are considered therapeutic drugs for tumors, there have been few clinical studies conducted on them.

Regional difference in spontaneous firing inhibition by GABA(A) and GABA(B) receptors in nigral dopamine neurons

GABAergic control over dopamine (DA) neurons in the substantia nigra is crucial for determining firing rates and patterns. Although GABA activates both GABA(A) and GABA(B) receptors distributed throughout the somatodendritic tree, it is currently unclear how regional GABA receptors in the soma and dendritic compartments regulate spontaneous firing. Therefore, the objective of this study was to determine actions of regional GABA receptors on spontaneous firing in acutely dissociated DA neurons from the rat using patch-clamp and local GABA-uncaging techniques. Agonists and antagonists experiments showed that activation of either GABA(A) receptors or GABA(B) receptors in DA neurons is enough to completely abolish spontaneous firing. Local GABA-uncaging along the somatodendritic tree revealed that activation of regional GABA receptors limited within the soma, proximal, or distal dendritic region, can completely suppress spontaneous firing. However, activation of either GABA(A) or GABA(B) receptor equally suppressed spontaneous firing in the soma, whereas GABA(B) receptor inhibited spontaneous firing more strongly than GABA(A) receptor in the proximal and distal dendrites. These regional differences of GABA signals between the soma and dendritic compartments could contribute to our understanding of many diverse and complex actions of GABA in midbrain DA neurons.

Tetramethylpyrazine protects learning memory of hypoxichypoxia rats through interfering expression of GABA receptor and FOXP2 / 中国药理学通报

Aim To examine the influence of tetramethylpyrazine on learning and memory function of hypoxic hypoxia rats, and the expression of gamma aminobutyric acid(GABA) receptor and forkhead box P2(FOXP2) in hippocampus of rats.Methods A total of 120 Sprague Dawley rats were randomly divided into low hypoxic hypoxia and high hypoxic hypoxia groups, then according to different time points every group was divided into 1 d, 3 d, 7 d 15 d, 30 d group, with 12 rats per each group.Experiment group and the control group were treated with tetramethylpyrazine and 0.9% normal saline, respectively.The hypoxic hypoxia environment was achieved by putting the rats in a hypobaric chamber at a simulated altitude of 5 500 meters for different days.The capabilities of learning and memory of rats were detected by Morris water maze test.The expression of GABA receptor and FOXP2 protein in hippocampus of rat was determined by Western blot.Results ① Morris water maze test showed that the total distance of rats in the simulated hypobaric hypoxia control group was longer than that in the tetramethylpyrazine group(P0.05);however,GABAB1 receptor and FOXP2 protein rose from the third day(P<0.05).The expression of GABAAα1 receptor and FOXP2 protein expression were correlated to total distance of Morris water maze in the control group(r=-0.738, P<0.05;r=-0.693, P<0.05), and the expression of GABAB1 receptor was correlated with FOXP2 protein level(r=0.834, P<0.05).Conclusion The simulated high-altitude hypobaric hypoxia can decrease the learning and memory abilities of rats, which may be ameliorated by tetramethylpyrazine intervention, and this effect might be related to the increase of GABAB1R receptor and FOXP2 expression in hippocampus of rats.

Progesterone upregulates GABAA receptor expression in the sympathetic center of rats with preeclampsia / 第二军医大学学报

Objective To observe the expression of GABAa receptor in rostral ventrolateral medulla (RVLM) of preeclampsia (PE) rats, so as to explore the role of GABAa receptor in the mechanisms by which progesterone improves cardiovascular dysfunction in PE rats. Methods Desoxycorticosterone acetate (DOCA) was intraperitoneally injected and 0. 9% normal saline (NS) replaced the normal drinking water in pregnant rats to establish rat PE model, and the models were verified by measuring the mean arterial pressure (MAP), heart rate (HR), renal sympathetic nerve activity (RSNA), and concentration of 24-h urine protein. And the modll rats were set as pregnant+DOCA+ saline (PDS) group. The other three groups included the nonpregnant rats (Con) group, nonpregnant rats receiving DOCA and saline (DS) group, and normal pregnant rats (NP) group. The PDS and NP groups were further divided into two subgroups according to different treatments: progesterone (17- OHPC) or NS administration, and the four groups were designated as NP+17-OHPC, NP+Veh, PDS+17-OHPC and PDS+ Veh groups. After three days of 17-OHPC treatment, the levels of progesterone in serum and cerebrospinal fluid were examined by the enzyme-linked immunosorbent assay (ELISA). The MAP, HR, RSNA and the 24-h urine protein were measured. Western blotting analysis was used to detect the protein expressions of GABAa receptor, GABAB receptor, and the nuclear progesterone receptors (nPGRA and nPGRB). Results Compared with Con, DS and NP groups, the MAP, RSNA and 24-h urine protein were increased significantly in PDS group (P<0. 05). Compared with NP group, progesterone levels in the serum and cerebrospinal fluid were significantly decreased in PDS group (P<0. 05). Three days after administration of progesterone to rats in PDS group, the MAP, RSNA and24-h urine protein were significantly reduced (P<0. 05), while the levels of progesterone in the serum and cerebrospinat fluid were significantly increased (P<0. 05). It was found that the expression of the GABAa receptor in RVLM was significantly decreased in PDS group compared with NP group (P<0. 05), which was reversed after 3 days’ administration of progesterone (P<0. 05). Compared with NP group, the expression of nPGRB was significantly increased in RVLM of rats in PDS group (P<0. 05), whereas progesterone treatment for 3 days produced a significant decrease of nPGRB (P<0. 05). The expressions of GABAB receptor and nPGRA were not significantly different between PDS and NP groups. Conclusion The expression of GABAA receptor is decreased in the RVLM of PE rats, which can be reversed by progesterone administration.

The effects of etomidate and midazolam on adipose tissue-derived mesenchymal stem cell proliferation / 대한마취과학회지

BACKGROUND: Stem cell therapy using adipose tissue-derived mesenchymal stem cells (ADSCs), which are capable of multipotent differentiation, is currently being investigated in the field of tissue regeneration and the treatment of patients in intensive care units. It is known that type-A γ-aminobutyric acid (GABA(A)) receptor activity has an influence on stem cell proliferation. Thus, we investigated the effects of the clinically available GABA(A) receptor agonists, etomidate and midazolam, on ADSC proliferation measured by the cell counting kit-8 assay. METHODS: ADSCs cultured in control medium or adipogenic differentiation medium for 15 days were divided into 5 treatment groups: non-medicated (Control) and 4 groups including treatment with etomidate or midazolam at 1 and 50 µM (n = 3 per group). The cell counting kit-8 assay was performed for determining the cell proliferation in both medium groups at day 0, 3, 6, 9, 12, and 15 in culture. The absorbance values at 450 nm were then measured by enzyme-linked immunosorbent assay reader and statistically compared among groups. RESULTS: There was no significant difference in cell proliferation profiles among the 5 groups at any time point in both control and adipogenic differentiation media. CONCLUSIONS: Etomidate and midazolam did not influence ADSC proliferation under both media when compared to the non-medicated group and there was no dose-dependent effect of etomidate and midazolam on ADSC viability.

Identification of a Novel GABAA Receptor Channel Ligand Derived from Melissa officinalis and Lavandula angustifolia Essential Oils.

Aims: Melissa officinalis (Mo) and Lavandula angustifolia (La) essential oils and their major constituents ((E) - caryophyllene, caryophyllene oxide, geranyl acetate, linalool, nerol, Oct-1-en-3-ol, 3-Octanone, myrcene, allo-ocimene, p-cymene and α- terpineol) assessed by GC-MS) which are shared by these two essential oils were probed in an attempt to identify the GABAAR ligand(s). Study Design: [35S] t-butylbicyclophosphorothionate (TBPS) radioligand binding assay to GABAA receptors. In vitro neuronal viability assay. Place and Duration of Study: School of Biological and Biomedical Sciences, Durham University, United Kingdom (December 2012 and January 2013). Results: One of the major component (s) of (Mo), trans-ocimene, inhibited [35S] (TBPS) binding to native GABAA receptors in a concentration-dependent manner with an apparent IC50 of 40μM. Concentrations (0.001 mg/ml) of whole (Mo) were shown to display modest beneficial effects upon neuronal viability while at a higher concentration (0.1 mg/ml) of (Mo) and (La) oils induced a neurotoxicity effect. Conclusion: These data provide the first evidence that allo-ocimene is an neuroactive GABAA R inhibitory component found in both (Mo) and (La), and represents a novel GABAA receptor channel chemotype derived from a natural product.

Impacto de la separación materna durante la lactancia sobre el tamaño del cerebro y la inmunorreacción al receptor Gaba ­ A / Impact of maternal separation during nursing on brain size and onGABA-Areceptorimmunoreactivity

Introducción. El vínculo materno es fundamental para el establecimiento y mantenimiento de las redes sinápticas, y el desarrollo morfofisiológico y emocional de los individuos. Los niños maltratados o rechazados son más propensos a desarrollar psicopatologías. Los modelos animales permiten una aproximación experimental a mecanismos involucrados en alteraciones ocasionadas por estrés temprano. Objetivo. Determinar si la separación materna durante la lactancia, afecta en el adulto el tamaño del cerebro y el número de células inmunorreactivas a la subunidad alfa 1 del recep-tor ácido gamma-aminobutírico: GABA-A. Métodos. Se mantuvieron ratas Wistar con ciclo invertido luz-oscuridad, sin restricciones de agua o comida. Durante la lactancia, a unas mamás les fueron separadas las crías dos veces al día y otras se mantuvieron como grupo control. El día 22 los sujetos se separaron por sexo y tratamiento. El día 60 se perfundieron con paraformaldehído, previa anestesia, y los cere-bros fueron extraídos y pesados. Para identificar el tamaño cerebral, se hicieron cinco cortes seriados de 20 µm cada 100 µm. Se tomaron fotografías y se utilizó una escala micrométrica. La inmunorreacción al receptor GABA-A se analizó en cortes de 20 µm mediante tinción por inmunohistoquímica. Resultados. En las ratas adultas, el peso cerebral total de las ratas separadas fue menor. En las hembras separadas se observó reducción estadísticamente significativa en el tamaño del hipocampo. En los machos separados se observó disminución de la marcación para la subunidad alfa1 del receptor GABA-A, en la corteza prefrontal, la amígdala y el hipocampo. Conclusiones. Estos resultados muestran que la separación materna durante la lactancia altera, en ciertas áreas cerebrales del adulto, el tamaño y la inmunorreacción al receptor GABA-A, y que estos cambios son diferentes en hembras y machos

Introduction: The maternal bond is crucial to establish and maintain synaptic networks and for morphophysiological and emotional development of individuals. Neglected or abused kids are more susceptible to develop psychopathologies. Animal models allow an experimen-tal approach to mechanisms involved in alterations due early stress. Objective:To determine if maternal separation during nursing alters brain size in adults and the amount of immunoreactive cells to alpha subunit of GABA-A receptor. Methods: Wistar rats were kept under reverse light-dark cycle with food and water ad libitum. During nursing, pups were separated from their mothers twice a day and other group was used as control. At day 22nd, subjects were separated by gender and treatment. In day 60, subjects were anesthetized and perfused with paraformaldehyde and brains were extracted and weighted. In order to identify brain size, 5 serial slides of 20 µm were made every 100 µm. Pictures were taken and micrometric scale was used. Immunoreactivity to alpha subunit of GABA-A receptor was analyzed in 20 µm slides through immunohistochemistry. Results: In adults, total brain weight of separated rats was inferior thanin the control group. Separated females showed a significant reduction of hippocampus size. In separated males a decrease of immunoreactivity to GABA-A receptor in prefrontal cortex, amygdala and hip-pocampuswas evidenced. Conclusions: These results show that maternal separation during nursing alterssize in some brain areas of adult rats, the immunoreactivity to alpha subunit of GABA-A receptor, and these changes are different between separated females and males.

The effects of γ-aminobutyric acid and sertraline on the GABA receptor of hippocampus neuron in rats of depression induced by acute stress / 中华行为医学与脑科学杂志

Objective To study the effects of γ-aminobutyric acid ( GABA) and sertraline on the CABAA(α) receptor and GABAB receptor of hippocampus neuron in rats of depression induced by acute stress. Methods The cognitive function of male SD (Sprague-Dawley) rats was screened through Y-maze. Then rats were randomly divided into five groups. Except control group,rats were injected intraperitoneally with double-distilled, GABA,sertraline or GABA + sertraline respectively. They were exposed to the forced-swimming stress test,which was to make acute stress model of depression. The space memory function in the maze was measured. Then the number of GABA-like immunoreactive neurons in hippocampus CA1 ,CA3 ,DG areas of rats were investigated with immunohistochemist. Results Compared with the model group,the immobility time in the forced-swimming test and the latency in the maze could be reduced significantly after pretreatment with GABA and sertraline (P < 0.01). The positive cell populations of CA1 ,CA3 region and DG gate region in the model group were significantly reduced compared with the control group (P<0.01). GABA could only improve the positive cell populations of GABAB receptor in CA3 region (P<0.01). In the sertraline group,the positive cell populations in hippocampus were increased obviously more than it in model group(P<0.01). The positive cell populations of hippocampus in the GABA + sertraline group in CA1 ( (82.83±8.72),(78.08±5.67)),in CA3((92.83±9.35),(76.00±3.97)),in the gate of DG( (35.00 ±1.41) ,(33.33±4.36)) increased significantly to the other groups (P< 0.05 or 0.01). Conclusion Ectogenic GABA could improve the sertraline' s effects of antagonizing acute depression effectively and the space memory function,and its mechanism may be involved in strengthening the expression of GABAA(α) receptor and GABAB receptor in hippocampus.

Anesthesia of a dental patient with Angelman syndrome: A case report / 대한마취과학회지

Angelman syndrome is characterized by a partial deficit of paired autosomal chromosome 15, which contains a subunit of the GABA (Gamma-Amino Butyric Acid) receptor. Many drugs that act on the CNS (Central Nerve System) during anesthesia are believed to exert their effects via the GABA receptors. We describe the anesthesia of a 7 year-old female patient with Angelman syndrome who underwent surgery for dental caries. The basic factors that needed to be considered when administering anesthesia to this patient were epilepsy, significant dominance of the vagal tone, craniofacial abnormalities and peripheral muscular atrophy. Inhalational anesthetics (sevoflurane) were employed for this patient. The patient had an uneventful peri-operative period and was discharged home on the same day of the operation.

Anesthesia of a dental patient with Angelman syndrome: A case report / 대한마취과학회지

Angelman syndrome is characterized by a partial deficit of paired autosomal chromosome 15, which contains a subunit of the GABA (Gamma-Amino Butyric Acid) receptor. Many drugs that act on the CNS (Central Nerve System) during anesthesia are believed to exert their effects via the GABA receptors. We describe the anesthesia of a 7 year-old female patient with Angelman syndrome who underwent surgery for dental caries. The basic factors that needed to be considered when administering anesthesia to this patient were epilepsy, significant dominance of the vagal tone, craniofacial abnormalities and peripheral muscular atrophy. Inhalational anesthetics (sevoflurane) were employed for this patient. The patient had an uneventful peri-operative period and was discharged home on the same day of the operation.

Effect of Sildenafil on Neuropathic Pain and Hemodynamics in Rats

PURPOSE: The inhibition of phosphodiesterase 5 produces an antinociception through the increase of cyclic guanosine monophosphate (cGMP), and increasing cGMP levels enhance the release of gamma-aminobutyric acid (GABA). Furthermore, this phosphodiesterase 5 plays a pivotal role in the regulation of the vasodilatation associated to cGMP. In this work, we examined the contribution of GABA receptors to the effect of sildenafil, a phosphodiesterase 5 inhibitor, in a neuropathic pain rat, and assessed the hemodynamic effect of sildenafil in normal rats. MATERIALS AND METHODS: Neuropathic pain was induced by ligation of L5/6 spinal nerves in Sprague-Dawley male rats. After observing the effect of intravenous sildenafil on neuropathic pain, GABAA receptor antagonist (bicuculline) and GABAB receptor antagonist (saclofen) were administered prior to delivery of sildenafil to determine the role of GABA receptors in the activity of sildenafil. For hemodynamic measurements, catheters were inserted into the tail artery. Mean arterial pressure (MAP) and heart rate (HR) were measured over 60 min following administration of sildenafil. RESULTS: Intravenous sildenafil dose-dependently increased the withdrawal threshold to the von Frey filament application in the ligated paw. Intravenous bicuculline and saclofen reversed the antinociception of sildenafil. Intravenous sildenafil increased the magnitude of MAP reduction at the maximal dosage, but it did not affect HR response. CONCLUSION: These results suggest that sildenafil is active in causing neuropathic pain. Both GABAA and GABAB receptors are involved in the antinociceptive effect of sildenafil. Additionally, intravenous sildenafil reduces MAP without affecting HR.

Association between γ-Aminobutyric Acid B2 Receptor Gene Polymorphism rs3750344 and Bone Mass Content or Bone Mass Density in Chinese Hans Population / 中国康复理论与实践

@# ObjectiveTo investigate the association of γ-aminobutyric acid B2 receptor (GABABR2) gene polymorphism rs3750344 and bone mass (bone mass content, BMC, and bone mass density, BMD) in population of Chinese Hans lives in Jinan. Methods425 volunteers were recruited. BMC and BMD of all subjects were measured with dual energy X-ray absorptiometry (DXA). Genotyping of polymorphism rs3750344 was conducted using Taqman assays. ResultsBMD and BMC increased with the copy of the C allele of rs3750344 in whole body. ConclusionThe C allele of GABABR2 rs3750344 increases the levers of BMD and BMC in Chinese Han population.

GABA Receptor Imaging / 핵의학분자영상

GABA is primary an inhibitory neurotransmitter that is localized in inhibitory interneurons. GABA is released from presynaptic terminals and functions by binding to GABA receptors. There are two types of GABA receptors, GABAA-receptor that allows chloride to pass through a ligand gated ion channel and GABAB-receptor that uses G-proteins for signaling. The GABAA-receptor has a GABA binding site as well as a benzodiazepine binding sites, which modulate GABAA-receptor function. Benzodiazepine GABAA receptor imaging can be accomplished by radiolabeling derivates that activates benzodiazepine binding sites. There has been much research on flumazenil (FMZ) labeled with 11C-FMZ, a benzodiazepine derivate that is a selective, reversible antagonist to GABAA receptors. Recently, 18F-fluoroflumazenil (FFMZ) has been developed to overcome 11C's short half-life. 18F-FFMZ shows high selective affinity and good pharmacodynamics, and is a promising PET agent with better central benzodiazepine receptor imaging capabilities. In an epileptic focus, because the GABA/benzodiazepine receptor amount is decreased, using 11C-FMZ PET instead of 18F-FDG PET, restrict the foci better and may also help find lesions better than high resolution MR. GABAA receptors are widely distributed in the cerebral cortex, and can be used as an viable neuronal marker. Therefore it can be used as a neuronal cell viability marker in cerebral ischemia. Also, GABA-receptors decrease in areas where neuronal plasticity develops, therefore, GABA imaging can be used to evaluate plasticity. Besides these usages, GABA receptors are related with psychological diseases, especially depression and schizophrenia as well as cerebral palsy, a motor-related disorder, so further in-depth studies are needed for these areas.

The Effect of Topiramate on Status Epilepticus-Induced Neurotoxicity in Immature Mouse Brain

PURPOSE:This study was performed to elucidate that status epilepticus (SE) induces long- term neuronal damages in an immature brain and to evaluate that topiramate (TPM) has a protective effect. METHODS:We investigated the changes in a subtype expression of glutamate and gamma- amino butyric acid (GABA) receptors, and the structural integrity due to cell losses in the mouse pup hippocampus after SE using an immunoblot and confocal microscopy. RESULTS:SE induced significant cell losses with structural changes in the hippocampus 1 month later. SE up-regulated the glutamate receptor1 (GluR1) expression with an increased ratio of GluR1 to glutamate recptor2 (GluR2), leading to the formation of Ca2+ permeable alpha- amino-3-hydroxy-5-methyl-4-isoxazoleepropionic acid (AMPA) receptors for the enhanced neurotoxicity. TPM prevented the SE-induced GluR1 expression. The expression of GABAA receptors was highly increased 1 month after SE, whereas that of GABAB receptors was not changed. The TPM treatment attenuated SE-induced upregulation of GABAA receptors. SE induced significant cell losses and disruption of structural integrity in the hippocampus CA1 and CA3 regions, but the TPM treatment for 1 month in developing brains reduced the SE- induced hippocampal damage. CONCLUSION:TPM has a neuroprotective action, which might be mediated by the modulation of GluR1 and GABAA receptors.

Spinal and Peripheral GABA-A and B Receptor Agonists for the Alleviation of Mechanical Hypersensitivity following Compressive Nerve Injury in the Rat / 대한통증학회지

BACKGROUND: This study was conducted to investigate the roles of the spinal and peripheral gamma-aminobutyric acid (GABA)-ergic systems for the mechanical hypersensitivity produced by chronic compression of the dorsal root ganglion (CCD). METHODS: CCD was performed at the left 5th lumbar dorsal root ganglion. The paw withdrawal threshold (PWT) to von Frey stimuli was measured. The mechanical responsiveness of the lumbar dorsal horn neurons was examined. GABAergic drugs were delivered with intrathecal (i.t.) or intraplantar (i.pl.) injection or by topical application onto the spinal cord. RESULTS: CCD produced mechanical hypersensitivity, which was evidenced by the decrease of the PWT, and it lasting for 10 weeks. For the rats showing mechanical hypersensitivity, the mechanical responsiveness of the lumbar dorsal horn neurons was enhanced. A similar increase was observed with the normal lumbar dorsal horn neurons when the GABA-A receptor antagonist bicuculline was topically applied. An i.t. injection of GABA-A or GABA-B receptor agonist, muscimol or baclofen, alleviated the CCD-induced hypersensitivity. Topical application of same drugs attenuated the CCD-induced enhanced mechanical responsiveness of the lumbar dorsal horn neurons. CCD-induced hypersensitivity was also improved by low-dose muscimol applied (i.pl.) into the affected hind paw, whereas no effects could be observed with high-dose muscimol or baclofen. CONCLUSIONS: The results suggest that the neuropathic pain associated with compression of the dorsal root ganglion is caused by hyperexcitability of the dorsal horn neurons due to a loss of spinal GABAergic inhibition. Peripheral application of low-dose GABA-A receptor agonist can be useful to treat this pain.

Effects of Nitric Oxide on Inhibitory Receptors of Rod Bipolar Cells of Rat Retina

The effects of nitric oxide (NO) on inhibitory neurotransmitter receptors and some types of inhibitory receptors in dissociated rod bipolar cell (RBC) were investigated. In the whole cell voltage-clamping mode, the gamma-aminobutyric acid (GABA) activated current showed both sustained and transient components. GABA activated transient current was fully blocked by bicuculine, a GABAA receptor antagonist. The cis-4-aminocrotonic acid (CACA), a GABAC receptor agonist, evoked the sustained current that was not blocked by bicuculline (BIC). Glycine activated the transient current. These results indicate that the RBCs possess GABAA, GABAC, and glycine inhibitory receptors. Sodium nitroprusside (SNP), a NO analogue, reduced the currents activated by GABAA receptor only, however, did not reduce the currents activated by either GABAC or glycine receptors. This study signifies further that only NO depresses the fast inhibitory response activated by GABAA receptor in RBC. We, therefore, postulate that NO might depress the light-on/off transient inhibitory responses in RBCs in the rat retina.

The Differential Manifestation of Alcohol Withdrawal Symptoms Related to GABAAalpha6 Polymorphism / 신경정신의학

INTRODUTION: The gamma-aminobutyric acid type A (GABAA) receptor is an important pharmacological target of alcohol. The phamacological characteristics of the receptor are largely determined by its subunit composition. Compared with all other alpha subtypes, the alpha6- containing receptors are more sensitive to GABA and less sensitive to benzodiazepines. The purpose of this study was to address a role for GABAAalpha6 receptor subunit gene in the development of alcohol dependence. The differential manifestation of alcohol withdrawal symptoms related to GABAAalpha6 polymorphism in patients treating with benzodiazepines was also examined. METHODS: Eighty-seven inpatients with alcohol dependence, and sixty healthy controls were evaluated using CIWA-Ar scale. Each patient was genotyped for GABAAalpha6 subunit. Association between GABAAalpha6 polymorphism and severity of withdrawal symptom were determined. RESULTS: No significant difference was found in GABAAalpha6 receptor genetic type and allelic distribution between the alcohol dependent and control subject. Tremor was more severe in CC than TT type. TT type had higher degree of anxiety, agitation and headache than CC type. The GABAAalpha6 C allele increased the average score of tremor significantly, and T allele increased that of agitation. CONCLUSION: The results suggested that GABAAalpha6 genetic polymorphism was not associated with alcohol dependence and with severity of alcohol withdrawal symptoms. But in benzodiazepine treated patients, GABAAalpha6 polymorphism and allelic type show the difference in severity of each withdrawal symptom. These differences of severity are partly responsible for the unique pharmacological properties associated with the GABAAalpha6 subunit.

Glutamate and GABA levels in the frontal cortex of rats with chronic epilepsy

Recently published data (Baran et al., Neurosignals 2004; 13: 290-7) have shown significantly increased activity of glutamic acid decarboxylase, the neuronal marker for gamma-aminobutyrate (GABA)-neurons, in the frontal cortex of rat brains, 6 months after kainic acid (KA) injection. In present study glutamate and GABA levels in the frontal cortex of rats in the KA (10 mg/kg, subcutaneously)-induced spontaneous recurrent seizure model of epilepsy, 6 months after the initial KA-induced seizures, were investigated. Six months after KA injection there was found a slightly reduced glutamate level in the frontal cortex (89.7 % of control), whereas the GABA level was moderately increased (119.6 % of control). The ratio GABA:glutamate level was significantly increased in the frontal cortex (134.5 % of control; P<0.001). Obtained data would indicate an enhancement of GABAergic activities in the frontal cortex in the chronic KA epileptic model. Interaction within GABAergic parameters, thus the GABAA receptors, the GABAB receptors, glutamate and GABA transporters may play a role in the modulation but also in the exertion of epileptic events in chronic KA epileptic model, which needs to be clarified.

Effects of gamma-Aminobutyric Acid on Intrinsic Cholinergic Action in Exocrine Secretion of Isolated, Perfused Rat Pancreas

gamma-Aminobutyric acid (GABA) has been reported to enhance exocrine secretion evoked not only by secretagogues but also by intrinsic neuronal excitation in the pancreas. The pancreas contains cholinergic neurons abundantly that exert a stimulatory role in exocrine secretion. This study was undertaken to examine effects of GABA on an action of cholinergic neurons in exocrine secretion of the pancreas. Intrinsic neurons were excited by electrical field stimulation (EFS; 15 V, 2 msec, 8 Hz, 45 min) in the isolated, perfused rat pancreas. Tetrodotoxin or atropine was used to block neuronal or cholinergic action. Acetylcholine was infused to mimic cholinergic excitation. GABA (30microM) and muscimol (10microM), given intra-arterially, did not change spontaneous secretion but enhanced cholecystokinin (CCK; 10 pM) -induced secretions of fluid and amylase. GABA (3, 10, 30microM) further elevated EFS-evoked secretions of fluid and amylase dose-dependently. GABA (10, 30, 100microM) also further increased acetylcholine (5microM) -induced secretions of fluid and amylase in a dose-dependent manner. Bicuculline (10microM) effectively blocked the enhancing effects of GABA (30microM) on the pancreatic secretions evoked by either EFS or CCK. Both atropine (2microM) and tetrodotoxin (1microM) markedly reduced the GABA (10microM) -enhanced EFS- or CCK-induced pancreatic secretions. The results indicate that GABA enhances intrinsic cholinergic neuronal action on exocrine secretion via the GABAA receptors in the rat pancreas.

The Effects of Repeated Stress on the GABAergic Neurotransmission in Rats / 신경정신의학

OBJECTIVES: Changes of GABAergic neurotransmission in response to the application of different types of environmental stress have been the subject of research for over two decades. However, the nature of the changes induced by stress appear to show a dependent phenomena on the type and duration of stressor agent employed. METHODS: For this reason, this study was performed to observe the effects of repeated stress on the radioligands binding to GABA A/benzodiazepine receptors of discrete brain regions. The author also examined the activity of GABA transaminase and the concentration of endogenous GABA. Male Sprague-Dawley rats, weighing 150-200g were forced to suffer an immobilization stress for 2 hours during 14 consecutive days. RESULTS: Repeated immobilization stress decreased the binding of [3H]flunitrazepam on the benzodiazepine receptor in the cortex, hippocampus and hypothalamus. Saturation experiments followed by scatchard analyses of the results showed decreased density of benzodiazepine receptor and the affinity remained unchanged. Repeated immobilization stress did not affect the binding of [3H]muscimol on the GABAA receptor, the activity of GABA transaminase, and the concentration of endogenous GABA in the brain regions. CONCLUSIONS: From these results, it can be concluded that repeated immobilization stress modulated GABAergic neurotransmission via downregulation of the benzodiazepine receptor in the brain.